Borbély Attila, van der Velden Jolanda, Papp Zoltán, Bronzwaer Jean G F, Edes Istvan, Stienen Ger J M, Paulus Walter J
Laboratory for Physiology, Institute for Cardiovascular Research, VUMC, Amsterdam, The Netherlands.
Circulation. 2005 Feb 15;111(6):774-81. doi: 10.1161/01.CIR.0000155257.33485.6D. Epub 2005 Feb 7.
Heart failure with preserved left ventricular (LV) ejection fraction (EF) is increasingly recognized and usually referred to as diastolic heart failure (DHF). Its pathogenetic mechanism remains unclear, partly because of a lack of myocardial biopsy material. Endomyocardial biopsy samples obtained from DHF patients were therefore analyzed for collagen volume fraction (CVF) and sarcomeric protein composition and compared with control samples. Single cardiomyocytes were isolated from these biopsy samples to assess cellular contractile performance.
DHF patients (n=12) had an LVEF of 71+/-11%, an LV end-diastolic pressure (LVEDP) of 28+/-4 mm Hg, and no significant coronary artery stenoses. DHF patients had higher CVFs (7.5+/-4.0%, P<0.05) than did controls (n=8, 3.8+/-2.0%), and no conspicuous changes in sarcomeric protein composition were detected. Cardiomyocytes, mechanically isolated and treated with Triton X-100 to remove all membranes, were stretched to a sarcomere length of 2.2 microm and activated with solutions containing varying [Ca2+]. Compared with cardiomyocytes of controls, cardiomyocytes of DHF patients developed a similar total isometric force at maximal [Ca2+], but their resting tension (F(passive)) in the absence of Ca2+ was almost twice as high (6.6+/-3.0 versus 3.5+/-1.7 kN/m2, P<0.001). F(passive) and CVF combined yielded stronger correlations with LVEDP than did either alone. Administration of protein kinase A (PKA) to DHF cardiomyocytes lowered F(passive) to control values.
DHF patients had stiffer cardiomyocytes, as evident from a higher F(passive) at the same sarcomere length. Together with CVF, F(passive) determined in vivo diastolic LV dysfunction. Correction of this high F(passive) by PKA suggests that reduced phosphorylation of sarcomeric proteins is involved in DHF.
左心室射血分数（EF）保留的心力衰竭越来越受到关注，通常被称为舒张性心力衰竭（DHF）。其发病机制尚不清楚，部分原因是缺乏心肌活检材料。因此，对从DHF患者获取的心内膜活检样本进行胶原容积分数（CVF）和肌节蛋白组成分析，并与对照样本进行比较。从这些活检样本中分离出单个心肌细胞，以评估细胞收缩性能。
DHF患者（n = 12）的左心室射血分数为71±11%，左心室舒张末压（LVEDP）为28±4 mmHg，无明显冠状动脉狭窄。DHF患者的CVF（7.5±4.0%，P<0.05）高于对照组（n = 8，3.8±2.0%），且未检测到肌节蛋白组成的明显变化。机械分离并用 Triton X - 100处理以去除所有膜的心肌细胞被拉伸至肌节长度2.2微米，并用含有不同[Ca2+]的溶液激活。与对照组心肌细胞相比，DHF患者的心肌细胞在最大[Ca2+]时产生的总等长力相似，但在无Ca2+时其静息张力（F（被动））几乎高出一倍（6.6±3.0对3.5±1.7 kN/m2，P<0.001）。F（被动）和CVF相结合与LVEDP的相关性比单独任何一个更强。向DHF心肌细胞施用蛋白激酶A（PKA）可将F（被动）降低至对照值。
DHF患者的心肌细胞更僵硬，在相同肌节长度下F（被动）更高即可证明。与CVF一起，F（被动）决定了体内左心室舒张功能障碍。PKA对这种高F（被动）的校正表明肌节蛋白磷酸化减少与DHF有关。
